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Taming the Autophagy As a Strategy for Treating COVID-19

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Taming the Autophagy As a Strategy for Treating COVID-19 cells Review Taming the Autophagy as a Strategy for Treating COVID-19 Blanca Estela García-Pérez 1,*, Juan Antonio González-Rojas 1, Ma Isabel Salazar 1, Carlos Torres-Torres 2 and Nayeli Shantal Castrejón-Jiménez 3 1 Department of Microbiology, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Prolongación de Carpio y Plan de Ayala S/N, Col. Santo Tomás, Alcaldía Miguel Hidalgo, Mexico City 11340, Mexico; [email protected] (J.A.G.-R.), [email protected] (M.I.S.) 2 Sección de Estudios de Posgrado e Investigación, Escuela Superior de Ingeniería Mecánica y Eléctrica, Unidad Zacatenco, Instituto Politécnico Nacional, Gustavo A. Madero, Mexico City 07738, Mexico; [email protected] 3 Área Académica de Medicina Veterinaria y Zootecnia, Instituto de Ciencias Agropecuarias-Universidad Autónoma del Estado de Hidalgo, Av. Universidad km. 1. Exhacienda de Aquetzalpa A.P. 32, Tulancingo, Hidalgo 43600, Mexico; [email protected] * Correspondence: [email protected] or [email protected]; Tel.: +52-553-988-7773 (ext. 46209) Received: 4 November 2020; Accepted: 8 December 2020; Published: 13 December 2020 Abstract: Currently, an efficient treatment for COVID-19 is still unavailable, and people are continuing to die from complications associated with SARS-CoV-2 infection. Thus, the development of new therapeutic approaches is urgently needed, and one alternative is to target the mechanisms of autophagy. Due to its multifaceted role in physiological processes, many questions remain unanswered about the possible advantages of inhibiting or activating autophagy. Based on a search of the literature in this field, a novel analysis has been made to highlight the relation between the mechanisms of autophagy in antiviral and inflammatory activity in contrast with those of the pathogenesis of COVID-19. The present analysis reveals a remarkable coincidence between the uncontrolled inflammation triggered by SARS-CoV-2 and autophagy defects. Particularly, there is conclusive evidence about the substantial contribution of two concomitant factors to the development of severe COVID-19: a delayed or absent type I and III interferon (IFN-I and IFN-III) response together with robust cytokine and chemokine production. In addition, a negative interplay exists between autophagy and an IFN-I response. According to previous studies, the clinical decision to inhibit or activate autophagy should depend on the underlying context of the pathological timeline of COVID-19. Several treatment options are herein discussed as a guide for future research on this topic. Keywords: SARS-CoV-2; COVID-19; autophagy; inflammation; cytokine storm; obesity 1. Introduction The pandemic of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) represents an enormous challenge for the scientific community around the world. There are numerous reports on the origin of the new virus as well as the diagnosis, prevention, and treatment of its associated disease. The suggested therapeutic regimens have been subjected to clinical studies, finding positive outcomes in some cases and a lack of significance (compared to standard care) in others (Table1). Since the drugs at this time administered to treat COVID-19 patients do not have significant efficacy to counteract the effects of the disease, new therapeutic options are urgently needed to control the infection to avoid fatal outcomes in hospitalized patients that have developed a severe infection. Cells 2020, 9, 2679; doi:10.3390/cells9122679 www.mdpi.com/journal/cells Cells 2020, 9, 2679 2 of 27 Table 1. The main treatments that have been administered to COVID-19 patients. Treatments Mechanisms of Action Type of Study Main Results Ref. (a) No association with A monophosphoramidate (a) Clinical trial statistically significant prodrug of an adenosine (a) [1] Remdesivir (b) clinical benefits. analogue that inhibits viral (b) [2] Compassionate use (b) Clinical improvement in RNA polymerases 36 of 53 patients (68%). A co-formulation of two structurally related No significant benefit from the protease-inhibitors as Lopinavir/Ritonavir Clinical trial treatment compared to [3] antiretroviral agents standard care. (HIV type 1 aspartate protease inhibitors) Inhibits the RNA-dependent RNA Attenuated disease progression Favipiravir plus IFN-α Open label control study [4] polymerase (RdRp) of and improved viral clearance. RNA viruses A synthetic derivative of a Compared to the DMSO-treated macrocyclic lactone In-vitro antiviral activity control, a 93% reduction in viral Ivermectin antiparasitic agent. [5] against SARS-CoV-2 RNA and a 99.9% in Inhibits the nuclear import cell-associated viral RNA. of host and viral proteins Both drugs accumulate in lysosomes, leading to (a) No significant difference elevated intra-vesicular between patients with pH that prevents hydroxychloroquine + (a) Prospective endosome trafficking and conventional treatment and randomized trial viral fusion. They also those with the conventional (a) [6] Hydroxychloroquine and (b) A pilot interfere with the treatment alone. (b) [7] Chloroquine observational study glycosylation of (b) Clinical improvement in all (c) [8] (c) Discontinued by ACE-2 receptors, participating patients receiving WHO which prevents their co-administration of binding by hydroxychloroquine with SARS-CoV-2 and azithromycin. thus infection. IFN-β1a and IFN-α2b are currently being evaluated as A broad-spectrum Interferon (IFN)-α Clinical trials in process potential candidates for the [9] antiviral agent treatment of patients with COVID-19. (a) A significant increase in the conversion rate from positive to negative results for the (a) Retrospective coronavirus test on days 7 and By inhibiting the cohort study 14 for patients receiving arbidol virus-mediated fusion (b) Cohort of 50 patients plus lopinavir/ritonavir versus (a) [10] Arbidol/lopinavir/ritonavir with the target membrane, in two groups: monotherapy with (b) [11] arbidol blocks virus entry lopinavir/ritonavir lopinavir/ritonavir. into the target cells regimen (34 cases) and (b) After 14 days of treatment, arbidol alone (16 cases) there was no viral load for the arbidol-treated group, but a 44.1% viral load for the lopinavir/ritonavir-treated group. (a) No attenuation of the disease in critically ill patients after a single dose of tocilizumab. A humanized (a) Retrospective (b) A rapid and sustained (a) [12] anti-interleukin-6-receptor observational study positive response to Tocilizumab (b) [13] (IL-6R) monoclonal (b) Cohort of 100 patients tocilizumab treatment. (c) [14] antibody that inhibits IL-6 (c) Retrospective study (c) Alleviation of the clinical symptoms and avoidance of severe COVID-19 with tocilizumab treatments. (a) Effective in alleviating (a) Evaluation of patient symptoms Appears to 6 COVID-19 patients and ameliorating exhibit a neutralizing (b) Case series analysis radiological injuries. (a) [15] Convalescent antibody response directed of 5 critically ill patients (b) Improved clinical status (b) [16] plasma therapy against the viral S protein. (c) Open-label, of patients. (c) [17] The antibodies block multi-center, (c) No statistically significant SARS-CoV-ACE2 entry. randomized clinical trial improvement in the clinical condition of patients. Anti-inflammatory effects are due to a negative Suppressed lung inflammation Corticosteroids Cohort of 41 patients [18] regulatory mechanism in 21% of patients. (transrepression). Cells 2020, 9, 2679 3 of 27 Table 1. Cont. Treatments Mechanisms of Action Type of Study Main Results Ref. The primary endpoints included symptom improvement and virus nucleic acid turning Prezcobix HIV protease inhibitor Under clinical trials [19] negative, but the optimal endpoint has not been determined. (a) COVID-19 (a) Recovery rate: 31%; patients (75) Mortality rate: 11%. (a) [20] Oseltamivir Neuraminidase inhibitor. (b) Non-severe (b) No significant improvement (b) [21] and severe in the clinical condition COVID-19 patients (393) of patients. The pathogenesis of COVID-19 is complex and poorly understood. It is manifested as a wide spectrum of symptoms and complications, including pneumonia, acute respiratory distress syndrome (ARDS) and endothelial dysfunction [18,22,23]. The condition of symptomatic infected individuals ranges from mild to severe. One of the components linked to severe cases of COVID-19 is an excessive host immune response characterized by uncontrolled inflammation derived from cytokine storm syndrome [18,24,25]. Of considerable concern is the relation between the development of severe COVID-19 and comorbidities among the elderly, especially obesity, hypertension, and diabetes. According to research on the mechanisms of COVID-19, one of the fundamental cell processes in the pathogenicity of the disease could possibly be autophagy. This sophisticated, highly orchestrated process represents an essential activity of cell remodeling and maintenance. Autophagy is responsible for selectively eliminating dysfunctional organelles, intracellular pathogens and misfolded proteins as well as regulating the immune response [26–29]. On the other hand, defective autophagy is associated with obesity, cancer, neurodegenerative disorders and autoimmune and infectious diseases [30–34]. Additionally, autophagic activity declines in the elderly [35]. However, no consensus exists on the usefulness of inhibiting or stimulating this mechanism to restrict the replication of SARS-CoV-2 to limit the clinical complications of COVID-19. The main
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